The impact of chemotherapeutic intervention in psychiatric disorders in the last century has been profound. Dramatic scientific progress towards understanding the basic biochemical mechanisms of action of these agents has been made. Despite these advances, vast areas of understanding still remain to be uncovered. Insight into the outcomes from the summation of numerous interactions with various receptors and receptor subtypes promises to lead to the invention of powerful neuroactive medicines.
A variety of simple tetrahydro-β-carboline compounds have been found in natural sources and some of these compounds have been associated with neurological activities. Rommelspacher, H. et. al. Beta-carbolines and tetrahydroisoquinolines: detection and function in mammals. Planta Med. 1991, 57(7), S85-92. Produced naturally via a Pictet-Spengler condensation reaction between indoleamines and aldehydes, these molecules have been observed in mammalian tissues and their association with food sources has led to speculation about their potential biological effects in chocolate and alcohol cravings. Herraiz, T. Tetrahydro-b-carbolines, potential neuroactive alkoloids, in chocolate and cocoa. J. Agric. Food Chem. 2000, 48, 4900-4904; Adell, A; Myers, R. D. Increased alcohol intake in low alcohol drinking rats after chronic infusion of the b-carboline Harman into the hippocampus. Pharmacol. Biochem. Behav. 1994, 49, 949-953.
The N-methyl-D-aspartate (NMDA) receptors are multi-subunit, ligand-gated ion channels with multiple regulatory sites around the central ion channel. These receptors gate Na+, Ca2+ and K+ ions into and out of cells. They are widely distributed in the central nervous system. NMDA receptors are activated by glutamate resulting in cation flux and cell depolarization. See Ozawa, et al., Glutamate receptors in the mammalian central nervous system. Prog. Neurobiol. 1998, 54, 581-618.
NMDA activation is believed to play an important role in learning and memory. However, over-activation can result in excitotoxic neuronal damage. For this reason antagonists of NMDA activation have been proposed as therapeutics for Alzheimer's disease and Parkinson's disease. See Choi, Glutamate neurotoxicity and diseases of the nervous system. Neuron 1988, 8, 623-634.
NMDA antagonists have also shown utility as possible therapeutics in pain, (see Parsons, NMDA receptors as targets for drug action in neuropathic pain. Eur. J. Pharmacol. 2001, 429, 71-78), depression and anxiety (see Rogoz, et al. Synergistic effect of uncompetitive NMDA receptor antagonists and antidepressant drugs in the forced swimming test in rates. Neuropharmacol. 2002, 42, 1024-1030).
Mutiple polyamine binding sites on the N-methyl-D-aspartate (NMDA) receptor-channel have the ability to modulate NMDA activity. See Williams, et al. Minireview. Modulation of the NMDA receptor by polyamines. Life Sciences 1991, 48(6), 469-498; and Sharma, et al. Characterization of the effects of polyamines on [125]MK-801 binding to recombinant N-methyl-D-aspartate receptors. J. Pharmacol. Exper. Therap. 1999, 289(2), 1041-1047.
Antagonism at the polyamine binding sites may prevent the NMDA receptor from being over-stimulated. See Worthen, et al. Endogenous indoles as novel polyamine site ligands at the N-methyl-D-aspartate receptor complex. Brain Res. 2001, 890, 343-346.
A major advantage in using polyamine site-specific NMDA antagonists lies in their ability to modulate without completely blocking NMDA receptor activation. Polyamines and polyamine analogs also have effect on non-NMDA glutamate receptors. See Chao, et al. N1− dansyl-spermine and N1-(n-octanesulfonyl)-spermine, novel glutamate receptor antagonists: Block and permeation of N-methyl-D-aspartate receptors. Molec. Pharmacol. 1997, 51, 861-871.
NMDA antagonists, other than polyamine analogs, have also been proposed for possible therapeutic application in depression and anxiety. See Trullas, et al. Functional antagonists of the NMDA receptor comples exhibit antidepressant action. Eu. J Pharmacol. 1990, 185, 1-10; Moryl, et al. Potential antidepressive properties of amantadine, memantine and bifemelane. Pharma. and Tox. 1993, 72, 394-397; and Skolnick, Antidepressants for the new millennium. Eur. J Pharmacol. 1999, 375, 31-40.
The NMDA receptor antagonist memantine has been shown to antagonize the 5-HT3 receptor and that may account for its antidepressant effects. See Rammes, et al. The NMDA receptor channel blockers memantine, neramexane and other amino-alkyl-cyclohexanes also antagonize 5-HT3 receptor currents in HEK-293 and N1E-115 cells in a uncompetitive manner. Neuroscience Lett. 2001, 306, 81-84; and Parsons, et al. Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist—a review of preclinical data. Neuropharmacology 1999, 38, 735-767.
Other competitive antagonists of NMDA receptors, e.g. CGP 37849 or AP-7, also show anti-depression effects in the forced swimming test in rates. See Maj. NMDA receptor antagonists and antidepressant drugs. Pharmacol Res. 1992, 25, R1.
NMDA antagonists used in conjunction with antidepressants have shown synergistic anti-depressant effects and may be particularly useful for drug-resistant depression. See Rogoz et al., supra.
Improved effects may be seen with other combination therapies such as antagonists at the polyamine and glycine sites for treating therapy-resistant complex partial seizures. See Wlax et al. Anticonvulsant effects of eliprodil alone or combined with the glycineB receptor antagonist L-701, 324 or the competitive NMDA antagonist CGP 40116 in the amygdala kindling model in rats. Neuropharmaco. 1999, 38, 243-251.
Improvements in CNS drugs may involve identifying the active stereochemical isomer, as in the case of eliprodil, a ligand selective for the NR2B subunit of the NMDA receptor. See Pabel, et al. Synthesis and resolution of racemic eliprodil and evaluation of the enantiomers of eliprodil as NMDA receptor antagonists. Bioorganic & Med. Chem. Lett. 2000, 10, 1377-1380.
In addition, antidepressants may work through interactions with various 5-HT receptors. See Kilpatrick, et al. Affinities of 5-HT uptake inhibitors for 5-HT3 receptors in both binding and functional studies. Brit J. Pharmacol. 1989, 98 (Suppl.): 859; Lucchelli, et al. The interaction of antidepressant drugs with central and peripheral (enteric) 5-HT3 and 5-HT4 receptors. Brit J. Pharmacol. 1995, 114, 1017-1025; and Glennon, Higher-end serotonin receptors: 5-HT5, 5-HT6, and 5-HT7. J. Med. Chem. 2003, 46, 2795-2812.
Serotonin (5-HT: 5 hydroxytryptamine) is a small molecule neurotransmitter whose actions and concentrations are regulated through receptors and cellular transporters. See Hoyer, et al. Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacology, Biochem. and Behavior 2002, 71, 533-554.
Serotonin, acting through its various receptors, is implicated in numerous disease states: depression, anxiety, schizophrenia, migraines, eating disorders, panic, hypertension, vomiting, social phobias, obsessive-compulsive disorders, pulmonary hypertension, and irritable bowel syndrome. See Hoyer, et al. supra. The 5-HT transporter is the target for selective serontonin reuptake inhibitors, an important class of antidepressants. There are seven families of receptors (5-HT1-7) based on their structure, operation and transduction. Furthermore, there are numerous subtypes of each family of 5-HT receptor. One of the families, 5-HT3, is a ligand-gated ion channel while the others are G-protein-systems, the gut cardiovascular system and blood. Receptor subtypes show specific localization patterns.
Furthermore, glutamate neurotransmission has been implicated in anxiety and depression. Antagonists of group I metabotropic glutamate receptors (mGluR), group II MGluR22 and group III mGluR23 have potential use against depression and anxiety. See Pilc, et al. Multiple MPEP administrations evoke anxiolytic-and antidepressant-like effects in rats. Neuropharma. 2002, 43(2), 181-187; Chjnacka-Wojcik, et al. Glutamate receptor ligands as anxiolytics. Curr Opin Investig Drugs. 2001, 2(8), 1112-1119; and Cryan, et al. Antidepressant and anxiolytic-like effects in mice lacking the group III metabotropic glutamate receptor MGluR7. Eur J Neurosci. 2003, 17(11), 2409-2417; respectively.
Notwithstanding the above providing new treatments for neurological diseases would be desirable.